Phthalazinones

ABSTRACT

The compounds of formula I 
                         
in which R1, R2, R3, R4 and R5 have the meanings as given in the description are PDE4/7 inhibitors.

This application was filed under 35 U.S.C. 371 and is the U.S. nationalstage of PCT/EP02/04438, filed Apr. 23, 2002.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel phthalazinone-derivatives, which are usedin the pharmaceutical industry for the production of medicaments.

KNOWN TECHNICAL BACKGROUND

International Patent Applications WO98/31674, WO99/31071, WO99/31090 andWO99/47505 disclose phthalazinone derivatives having selective PDE4inhibitory properties. In the International patent applicationWO01/19818 phthalazinone derivatives with PDE3/4 inhibitory propertiesare disclosed. In the International Patent Application WO94/12461 and Inthe European Patent Application EP 0 763 534 3-aryl-pyridazin-6-one andarylalkyl-diazinone derivatives are described as selective PDE4inhibitors.

DESCRIPTION OF THE INVENTION

It has now been found that the phthalazinone-derivatives, which aredescribed in greater details below, have surprising and particularlyadvantageous properties.

The invention thus relates to compounds of formula I

in which

-   R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or    predominantly substituted by fluorine,-   R2 is fluorine, bromine or chlorine,-   R3 and R4 are both hydrogen or together form an additional bond,-   R5 is R6, —C_(m)H_(2m)—R7, —C_(n)H_(2n)—C(O)R8, —CH(R9)₂,    —C_(p)H_(2p)—Y-Aryl1, R12 or R26, in which-   R6 1-8C-alkyl, 3-10-cycloalkyl, 3-7C-cycloalkylmethyl, 3-7C-alkenyl,    3-7C-alkinyl, phenyl-3-4C-alkenyl, 7-10C-polycycloalkyl, naphthyl,    pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, quinazolinyl,    quinoxalinyl, cinnolinyl, isoquinolinyt, quinolinyl, indanyl,    indazolyl, benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl,    N-methylpiperidyl, tetrahydropyranyl,    6-methyl-3-trifluoromethyl-pyridin-2-yl,    1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,    3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,    1,1-dioxide-tetrahydrothlophen-3-yl,    1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4yl-but-1-oxy)-benzoic    acid, or an unsubstituted or by R61 and/or R62 substituted phenyl    radical, in which-   R61 is hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, nitro, cyano, halogen,    carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C-alkoxycarbonyl,    hydroxy-1-4C-alkyl, amino, mono- or di-1-4C-alkylamino,    1-4C-alkylcarbonylamino, aminocarbonyl, mono- or    di-1-4C-alkylaminocarbonyl, aminosulfonyl, mono- or    di-1-4C-alkylaminosulfonyl, 4-methylphenylsulfonamido, imidazolyl,    tetrazol-5-yl, 2-(1-4C-alkyl)tetrazol-5-yl or 2-benzyl-tetrazol-5-yl    and-   R62 is 1-4C-alkyl, 1-4C-alkoxy, nitro or halogen,-   R7 is hydroxyl, halogen, cyano, nitro, nitroxy(—O—NO₂), carboxyl,    carboxyphenyloxy, phenoxy, 1-4C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy,    1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, aminocarbonyl, mono-    or di-1-4C-alkylaminocarbonyl, amino, mono- or di-1-4C-alkylamino,    or an unsubstituted or by R71 and/or R72 substituted piperidyl,    piperazinyl, pyrrolidinyl or morpholinyl radical, where-   R71 is hydroxyl, 1-4C-alkyl, hydroxy-1-4C-alkyl or    1-4C-alkoxycarbonyl, and-   R72 is 1-4C-alkyl, carboxyl, aminocarbonyl or 1-4C-alkoxycarbonyl,-   R8 is an unsubstituted or by R81 and/or R82 substituted phenyl,    naphthyl, phenanthrenyl or anthracenyl radical, in which-   R81 is hydroxyl, halogen, cyano, 1-4C-alkyl, 1-4C-alkoxy, carboxyl,    aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,    1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, or 1-4C-alkoxy which is    completely or predominantly substituted by fluorine, and-   R82 is hydroxyl, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy    which is completely or predominantly substituted by fluorine,-   R9 is —C_(q)H_(2q)-phenyl,-   Y is a bond or O (oxygen),-   Aryl1 is an unsubstituted phenyl, naphthyl, pyridyl, pyrazinyi,    pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl,    isoquinolyl, quinolyl, coumarinyl, benzimidazolyl, benzoxazolyl,    benzothiazolyl, benzotriazolyl, N-benzosuccinlmldyl, imidazolyl,    pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, a    2-(1-4C-alkyl)-thiazol-4-yl radical, or a phenyl radical substituted    by R10 and/or R11, in which-   R10 is hydroxyl, halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl,    1-4C-alkoxy, carboxyl, hydroxycarbon yl-1-4C-alkyl,    1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or    di-1-4C-alkylamino-carbonyl, imidazolyl or tetrazolyl, and-   R11 is hydroxyl, halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy,-   m is an integer from 1 to 8,-   n is an integer from 1 to 4,-   p is an integer from 1 to 6,-   q is an integer from 0 to 2,-   R12 is a radical of formula (a)

wherein

-   R13 is —S(O)₂—R14, —S(O)₂—(CH₂)_(r)—R15, —(CH₂)_(s)—S(O)₂—R16,    —C(O)R17, —C(O)—(CH₂)_(r)—R18, —(CH₂)_(s)—C(O)—R19, Hetaryl1, Aryl2    or Aryl3-1-4C-alkyl,-   R14 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R20)R21,    phenyl or phenyl substituted by R22 and/or R23,-   R15 is —N(R20)R21,-   R16 is —N(R20)R21,-   R17 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl,    4-ethyl-piperazin-2,3-dion-1-yl, 2-oxo-imidazolidin-1-yl or    —N(R20)R21,-   R18 is —N(R20)R21,-   R19 is —N(R20)R21, phenyl, phenyl substituted by R22 and/or R23    and/or R24,-   R20 and R21 are independent from each other hydrogen, 1-7C-alkyl,    3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or phenyl, or R20 and R21    together and with inclusion of the nitrogen atom to which they are    bonded, form a 4-morpholinyl-ring, 1-pyrrolidinyl-ring,    1-piperidinyl-ring, 1-hexahydroazepino-ring or a 1-piperazinyl-ring    of formula (b)

-   -   wherein    -   R25 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino,        dimethylaminocarbonyimethyl, N-methyl-piperidin-4-yl,        4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,

-   R22 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl,    1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino,    aminocarbonyl 1-4C-alkylcarbonylamino or mono-or    di-1-4C-alkylaminocarbonyl,

-   R23 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,

-   R24 is halogen,

-   Hetaryl1 is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl,    1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl, thiazolyl, imidazolyl or    furanyl,

-   Aryl2 is pyridyl, phenyl or phenyl substituted by R22 and/or R23,

-   Aryl3 is pyrldyl, phenyl, phenyl substituted by R22 and/or R23,    2-oxo-2H-chromen-7-yl or 4-(1,2,3-thladiazol4-yl)phenyl,

-   r is an integer from 1 to 4,

-   s is an integer from 1 to 4,

-   R26 is a radical of formula (c)

wherein

-   R27 is —C(O)R28, —(CH₂)_(t)—C(O)R29, —(CH₂)_(u)R30, Aryl4, Hetaryl2,    phenylprop-1-en-3-yl or 1-methylpiperidin-4yl,-   R28 hydrogen, 1-4C-alkyl, —OR31, furanyl, indolyl, phenyl, pyridyl,    phenyl substituted by R34 and/or R35 or pyridyl substituted by R36    and/or R37,-   R29 is —N(R32)R33,-   R30 is —N(R32)R33, tetrahydrofuranyl or pyridinyl,-   R31 is 1-4C-alkyl,-   R32 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or    3-7C-cycloalkylmethyl,-   R33 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or    3-7C-cycloalkylmethyl,-   or R32 and R33 together and with inclusion of the nitrogen atom to    which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-,    1-piperidinyl- or 1-hexahydroazepinyl-ring,-   Aryl4 is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R34    and/or R35, pyridyl substituted by R36 and/or R37,-   R34 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,-   R35 is halogen or 1-4C-alkyl,-   R36 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,-   R37 is halogen or 1-4C-alkyl,-   Hetaryl2 is indol4-yl, 2-methyl-quinolin-4-yl,    5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,    3-phenyl-1,2,4-thladiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl,-   t is an integer from 1 to 4,-   u is an integer from 1 to 4,-   v is an integer from 1 to 2,-   X is —C(O)— or —S(O)₂—,    and the salts of these compounds, with the proviso that the compound    (cis)-4-(3-Chloro4-methoxy-phenyl)2-cycloheptyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    is excluded.

1-8C-Alkyl is a straight-chain or branched alkyl radical having 1 to 8carbon atoms. Examples are the octyl, heptyl, isoheptyl (5-methylhexyl),hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl),neopentyl (2,2-dimethylpropyl), pentyl, isopentyl (3-methylbutyl),1-ethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl and methyl radicals.

1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, ethyl and methyl radicals.

1-4C-Alkoxy is a radical, which, in addition to the oxygen atom containsa straight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned inthis context are, for example, the butoxy, iso-butoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

1-4C-Alkoxy which is completely or predominantly substituted by fluorineis, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy,the 1,2,2-trifluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical. “Predominantly” inthis connection means that more than half of the hydrogen atoms of the1-4C-alkoxy groups is replaced by fluorine atoms.

1-2C-Alkoxy which is completely or predominantly substituted by fluorineis, for example, the 1,1,2,2-tetrafluoroethoxy, the2,2,2-trifluoroethoxy and in particular the trifluoromethoxy and thedifluoromethoxy radical.

1-8C-Alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 8 carbon atoms.Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned inthis context are, for example, the octyloxy, heptyloxy, isoheptyloxy(5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy),neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy(3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxyradicals.

3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of whichcyclopropylmethoxy, cyclobutylmethoxy and cyclopen-tylmethoxy arepreferred.

3-10C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.

3-7C-Cycloalkylmethyl stands for a methyl radical, which is substitutedby one of the abovementioned 3-7C-cycloalkyl radicals. Examples whichmay be mentioned are the cyclopropylmethyl, the cyclopentylmethyl andthe cyclohexylmethyl radicals.

3-7C-Alkenyl is a straight chain or branched alkenyl radical having 3 to7 carbon atoms. Preferred examples are the 2-butenyl, 3-butenyl,1-propenyl and the 2-propenyl (allyl) radicals.

3-7C-Alkinyl is a straight chain or branched alkinyl radical having 3 to7 carbon atoms. Preferred examples are the 2-penfinyl, 2-butinyl,3-butinyA and the 2-propinyl (propargyl) radicals.

7-10C-Polycycloalkyl stands for 7-10C-bicycloalkyl or7-10C-tricycloalkyl radicals, such as for example, bomyl, norbornyl oradamantyl.

A Phenyl-3-4C-alkenyl radical is, for example, the phenylprop-1-en-3-ylradical.

Halogen within the meaning of the present invention is bromine, chlorineand fluorine.

1-4C-Alkylcarbonyl is a carbonyl group to which one of theabovementioned 1-4Calkyl radicals is bonded. An example is the acetylradical [CH₃C(O)—].

1-4C-Alkylcarbonyloxy radicals contain, in addition to the oxygen atom,one of the abovementioned 1-4C-alkylcarbonyl radicals. An example is theacetoxy radical [CH₃C(O)—O—].

A 1-4C-Alkylcarbonylamino radical is, for example, the acetamido radical[—NH—C(O)—CH₃].

1-4C-Alkoxycarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkoxy radicals is bonded. Examples are theethoxycarbonyl [CH₃CH₂O—C(O)—] and the methoxycarbonyl [CH₃O—C(O)—]radicals.

Mono- or Di-1-4C-alkylaminocarbonyl radicals are, for example, themethylaminocarbonyl, the dimethylaminocarbonyl and thediethylaminocarbonyl radicals.

Mono- or Di-1-4C-alkylamino radicals are, for example, the methylamino,the dimethylamino and the diethylamino radicals.

Mono- or Di-1-4C-alkylaminosulfonyl stands for a sulfonyl group to whichone of the abovementioned mono- or di-1-4C-alkylamino radicals isbonded. Examples which may be mentioned are the methylaminosulfonyl, thedimethylaminosulfonyl and the ethylaminosulfonyl radical.

Hydroxy-1-4C-alkyl stands for one of the abovementloned 1-4C-alkylradicals which is substituted by hydroxyl. Examples which may bementioned are the hydroxymethyl radical, the 2-hydroxyethyl radical orthe 3-hydroxypropyl radical.

Hydroxycarbonyl-1-4C-alkyl radicals are, for example, thehydroxycarbonylmethyl [—CH₂C(O)OH] and the hydroxycarbonylethyl[—CH₂CH₂C(O)OH] radicals.

If R3 and R4 together form an additional bond, then the carbon atoms towhich R3 and R4 are attached are linked to one another via a doublebond.

The groups —C_(m)H_(m)—, —C_(n)H_(2n)—, —C_(p)H_(2p)— and —C_(q)H_(2q)—can be straight chain or branched groups. Examples which may bementioned for the —C_(m)H_(2m)— group are the octylene, heptylene,isoheptylene (2-methylhexylene), hexylene, isohexylene(2-methylpentylene), neohexylene (2,2-dimethylbutylene), butylene,isobutylene, sec-butylene, tert-butylene, propylene, isopropylene,ethylene, 1-methylmethylene and the methylene group.

Examples which may be mentioned for the —C_(p)H_(2p)— group are thehexylene, isohexylene (2-methylpentylene), neohexylene(2,2-dimethylbutylene), butylene, isobutylene, sec-butylene,tert-butylene, propylene, isopropylene, ethylene, 1-methylmethylene andthe methylene group.

Examples which may be mentioned for the —C_(m)H_(2m)— group are thebutylene, isobutylene, sec-butylene, tert-butylene, propylene,isopropylene, ethylene, 1-methylmethylene and the methylene group.

Examples which may be mentioned for the —C_(q)H_(2q)— group are theethylene, 1-methylmethylene and the methylene group. The group—C_(q)H_(2q)— represents a covalent bond in case of q is 0 (zero).

Aza-heterocyles which are a component (=Aryl1) of the group ofsubstituents defined as —C_(p)H_(2p)-Aryl1 and contain the grouping —NH—(imino), such as for example, pyrrole, imidazole, benzimidazole,benzotriazole or benzosuccinimide, are preferably bonded via theirimino-nitrogen to the above defined —C_(p)H_(2p)— group.

Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-soluble and water-insolubleacid addition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled In the art.

According to experts knowledge the compounds of the invention as well astheir salts may contain, e.g. when isolated in crystalline form, varyingamounts of solvents. Included within the scope of the invention aretherefore all solvates and in particular all hydrates of the compoundsof formula I as well as all solvates and in particular all hydrates ofthe salts of the compounds of formula I.

Compounds of formula I which are to be emphasized are those in which

-   R1 is methoxy or ethoxy,-   R2 is chlorine, bromine or fluorine-   R3 and R4 together form an additional bond,-   R5 is R6, —C_(m)H_(2m)—R7, —C_(p)H_(2p)—Y-Aryl1, R12 or R26 in which-   R6 3-6C-cycloalkyl, 3-7C-cycloalkylmethyl, quinoxalinyl, indazolyl,    benzothiazolyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,    1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,    3-thiophen-2-yl[1,2,4]-thiadiazol-5-yl,    1,1-dioxide-tetrahydrothiophen-3-yl,    1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4-yl-but-1-oxy)-benzoic    acid, or an unsubstituted or by R61 substituted phenyl radical, in    which-   R61 is 1-4C-alkyl, 1-4C-alkoxy, carboxyl or 1-4C-alkoxycarbonyl,-   R7 is carboxyphenyloxy,-   Y is a bond,-   Aryl1 is imidazolyl,-   m is an integer from 1 to 4,-   p is an integer from 1 to 4,-   R12 is a radical of formula (a)

wherein

-   R13 is —S(O)₂—R14, —C(O)R17 or Aryl3-1-4C-alkyl,-   R14 is phenyl or phenyl substituted by R22,-   R17 is 1-4C-alkyl, 2-oxo-imidazolidin-1-yl or —N(R20)R21,-   R20 and R21 are independent from each other 1-7C-alkyl, or R20 and    R21 together and with inclusion of the nitrogen atom to which they    are bonded, form a 4-morpholinyt, 1-pyrrolidinyl-, 1-piperidinyl- or    1-hexahydroazepino-ring,-   R22 is 1-4C-alkyl,-   Aryl3 is pyridyl,-   R26 is a radical of formula (c)

wherein

-   R27 is —(CH₂)_(u)R30,-   R30 is —N(R32)R33,-   R32 is 1-4C-alkyl,-   R33 is 1-4C-alkyl,-   or R32 and R33 together and with Inclusion of the nitrogen atom to    which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-,    1-piperidinyl- or 1-hexahydroazepinyl-ring,-   u is an integer from 1 to 4,-   v is 1,-   X is —C(O)—,    and the salts of these compounds.

Compounds of formula I which are particularly to be emphasized are thosein which

-   R1 is methoxy or ethoxy,-   R2 is chlorine, bromine or fluorine,-   R3 and R4 together form an additional bond,-   R5 is 1-(morpholin-4-yl-methanoyl)-piperidin-4-yl,    1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,    1-(pyridin-4-ylmethylypiperidin-4-yl,    4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,    quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,    1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,    3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,    1,1-dioxide-tetrahydrothiophen-3yl, benzothiazol-6-yl,    1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,    4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid,    4-hydroxycarbonylphenyl or    1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl,    and the salts of these compounds.

Preferred compounds of formula I are those in which

-   R1 is methoxy or ethoxy,-   R2 is chlorine,-   R3 and R4 together form an additional bond,-   R5 is 1-(morpholin-4-yl-methanoyl)-piperidinyl,    1-(toluene-4-sulfonyl)-piperidinyl, 1-acetyl-piperidin-4-yl,    1-(pyridin-4-ylmethyl)-piperidinyl,    4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}phenyl,    quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,    1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,    3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,    1,1-dioxide-tetrahydrothiophen-3-yl, benzothiazol-6-yl,    1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,    4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)benzoic acid,    4-hydroxycarbonylphenyl or    1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl,    and the salts of these compounds.

Further preferred compounds of formula I are

-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(1-morpholin-4yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-2-(1-Acetyl-piperidin-4-yl)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(6-methyl-3-trifluoromethyl-pyridin-2-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-2-Benzothiazol-6-yl-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro4-methoxy-phenyl)-2-(1H-indazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-cyclopentyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)2-(4-imidazol-1-yl-butyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-{4-[4-(3-Chloro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-butoxy}-benzoic    acid,-   (cis)-4-[4-(3-Fluoro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-benzoic    acid,-   (cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzoic    acid,-   (cis)-4-{4-(3-bromo-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}benzoic    acid,-   (cis)-4-(3-chloro-4-methoxy-phenyl)-2-quinoxalin-2-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)2-(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,1-dioxo-tetrahydro-1l(6)-thiophen-3-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4ethoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3Chloro-4-methoxy-phenyl)-2-phenyl-4a25,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-{1-[1-(2-oxo-imidazolidin-1-yl)-methanoyl]-piperidine-4-yl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,    and the salts of these compounds.

A special embodiment of the compounds of the present invention includethose compounds of formula I in which R1 is 1-2C-alkoxy, R2 is chlorine,R3 and R4 together form an additional bond and R5 is R6.

Another special embodiment of the compounds of the present Inventioninclude those compounds of formula I in which R1 is 1-2C-alkoxy, R2 ischlorine, R3 and R4 together form an additional bond and R5 is—C_(m)H_(2m)—R7.

A further special embodiment of the compounds of the present InventionInclude those compounds of formula I in which R1 is 1-2C-alkoxy, R2 ischlorine, R3 and R4 together form an additional bond and R5 is—C_(p)H_(2p)—Y-Aryl1.

Still another special embodiment of the compounds of the presentinvention include those compounds of formula I in which R1 is1-2C-alkoxy, R2 is chlorine, R3 and R4 together form an additional bondand R5 is R12.

Yet another special embodiment of the compounds of the present Inventioninclude those compounds of formula I in which R1 is 1-2C-alkoxy, R2 ischlorine, R3 and R4 together form an additional bond and R5 is R26.

The compounds of formula I are chiral compounds. Chiral centers exist inthe compounds of formula I in the positions 4a and 8a.

Numbering

Therefore the invention includes all conceivable pure diastereomers andpure enantiomers of the compounds of formula I, as well as all mixturesthereof independent from the ratio, including the racemates. Preferredare those compounds of formula I, in which the hydrogen atoms in thepositions 4a and 8a are cis-configurated. Especially preferred in thisconnection are those compounds, in which the absolute configuration(according to the rules of Cahn, Ingold and Prelog) is S in the position4a and R in the position 8a.

Racemates can be split up into the corresponding enanflomers by methodsknown by a person skilled in the art. Preferably the racemic mixturesare separated into two diastereomers during the preparation with thehelp of an optical active separation agent on the stage of thecyclohexanecarboxylic acids or the 1,2,3,6-tetrahydrobenzoic acids (forexample, starting compounds A5 and A6). As separation agents may bementioned, for example, optical active amines such as the (+)- and(−)-forms of 1-phenylethylamine[(R)-(+)-1-phenylethylamine=D-α-methylbenzylamine; or(S)-(−)-1-phenylethylamine=L-α-methylbenzylamine), ephedrine, theoptical active alkaloids quinine, cinchonine, cinchonidine and brucine.

The compounds according to the invention can be prepared, for example,as described in Reaction scheme 1, 2 or 3.

Compounds, in which R5 stands for R12 preferably prepared according toreaction scheme 2.

Compounds, in which R5 stands for R26 are preferably prepared accordingto reaction scheme 3.

Suitably, the conversions are carried out analogous to methods which arefamiliar per se to the person skilled in the art, for example, in themanner which is described in the following examples.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallising the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid, or to which thedesired acid is then added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification into the free compounds which, in turn, can be convertedinto salts. In this manner, pharmacologically non-tolerable salts can beconverted into pharmacologically tolerable salts.

The following examples illustrate the invention in greater detail,without restricting it. As well, further compounds of formula I, ofwhich the preparation is explicitly not described, can be prepared in ananalogous way or in a way which is known by a person skilled in the artusing customary preparation methods.

The compounds, which are mentioned in the examples as well as theirsalts are preferred compounds of the invention.

EXAMPLES Final Products 1.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 1.0 g of intermediate product A1 and 1.0 g ofmorpholine-4-carbonyl chloride in 50 ml of pyridine is stirred at RT for18 h after which the mixture is evaporated. The residue is partitionedbetween aqueous sodium carbonate and dichloromethane. Thedichloromethane layer is dried over magnesium sulfate and evaporated.The compound is crystailised from diethyl ether. M. p. 185–186° C.

2.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 1.0 g of intermediate product A1 and 1.0 g ofp-toluenesulfonyl chloride in 50 ml of pyridine is stirred at RT for 18h after which the mixture is evaporated. The residue is partitionedbetween aqueous sodium carbonate and dichloromethane. Thedichloromethane layer is dried over magnesium sulfate and evaporated.Crystallised from a mixture of ethyl acetate and petroleum ether (60-80°C.). M. p. 198–199° C.

3.(cis)-2-(1-Acetyl-piperidin-4-yl)-4-(3-chloro-4-methoxy-phenyl)-4a,5.8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 1.0 g of intermediate product A1 and 1.0 g of aceticanhydride in 50 ml of pyridine is stirred at RT for 18 h after which themixture is evaporated. The residue is partitioned between aqueous sodiumcarbonate and dichloromethane. The dichloromethane layer is dried overmagnesium sulfate and evaporated. Crystallised from ethyl acetate. M. p.206–208° C.

4.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

A mixture of 1.0 g of intermediate product A1, 1.0 g of4-picolylchloride hydrochloride and 1.0 g of potassium carbonate in 20ml of dimethylformamide is stirred for 18 h at RT after which 100 ml ofwater is added to the reaction mixture. The mixture is extracted withdiethyl ether. The ether solution is dried over magnesium sulfate. Afterthe addition of a saturated solution of hydrochloric acid in ether, thecompound precipitated. M. p. 244° C. (decomposition).

5.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

A mixture of 2 mmol of intermediate product A2, 2 mmol of1-(2-dimethylaminoethyl)-piperazine and 3 mmol of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 30 ml ofdimethylformamide is stirred for 18 h, after which the mixture is pooredinto aqueous sodium carbonate. This mixture is extracted with diethylether and the extract is dried over magnesium sulfate. Addition of asolution of hydrochloric acid in ether causes precipitation of the titlecompound. M. p.198–201° C.

6.(cis)-4-(3-Chloro-4-methoxy-phenyl-2-(6-methyl-3-trifluoromethyl-pyridin-2-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 12 mmol of6-methyl4trifluoromethyl-pyridin-2-yl)hydrazine, 10 mmol of startingcompound A6 and 1 g of pyridine hydrochloride in 50 ml of pyridine isrefluxed for 18 h after which the solvent is evaporated. The residue isdissolved in dichloromethane and this solution is washed with 1Nhydrochloric acid. The organic phase is dried over magnesium sulfate andevaporated. The residue is crystallised from diethyl ether. M. p.156–157° C.

7.(cis)-2-Benzothiazol-6-yl-4-(3-chloro-4-methoxy-phenyl)-4a,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 12 mmol of benzothiazol-6-ylhydrazine, 10 mmol of startingcompound A6 and 1 g of pyridine hydrochloride in 50 ml of pyridine isrefluxed for 18 h after which the solvent is evaporated. The residue isdissolved in dichloromethane and this solution is washed with 1Nhydrochloric acid. The organic phase is dried over magnesium sulfate andevaporated. The residue is crystallised from diethyl ether. M. p.156–157° C.

8.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 12 mmol of 5-hydrazino-3H-isobenzofuran-1-one, 10 mmol ofstarting compound A6 and 1 g of pyridine hydrochloride in 50 ml ofpyridine is refluxed for 18 h after which the solvent is evaporated. Theresidue is dissolved in dichloromethane and this solution is washed with1N hydrochloric acid. The organic phase is dried over magnesium sulfateand evaporated. The residue is crystallised from diethyl ether. M. p.212–213° C.

9.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1H-indazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

A solution of 12 mmol of 1H-indazol-5-ylhydrazine, 10 mmol of startingcompound A6 and 1 g of pyridine hydrochloride in 50 ml of pyridine isrefluxed for 18 h after which the solvent is evaporated. Afterevaporating the pyridine, the residue is dissolved in ethyl acetate andwashed with aqueous sodium carbonate. The solvent is dried overmagnesium sulfate and evaporated. The residue is dissolved in ethylacetate and to this solution, a solution of hydrochloric acid in etheris added. The precipitate is filtered off and dried. M p. 196-197° C.

10.(cis)-4-(3Chloro-4-methoxy-phenyl)-2-cyclopentyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

12 mmol of sodium hydride is added to a solution of 10 mmol ofintermediate product A3 in 50 ml of DMF. The resulting mixture isstirred for 30 min after which 10 mmol of chlorocyclopentane is added.The resulting mixture is stirred for 1 h and subsequently poured intowater. The precipitate is filtered off and crystallised from methanol.M. p. 201–202° C.

11.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-imidazol-1-yl-butyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

A mixture of 5 mmol of intermediate product A4 and 20 mmol of imidazolein 20 ml of DMF is stirred for 18 h at RT after which the solution ispoured into aqueous sodium carbonate. This solution is extracted withdiethyl ether. After drying over magnesium sulfate, a solution ofhydrochloric acid in ether is added. The precipitate is filtered off anddried. M. p. 217–219° C.

12.(cis)-4-{4-[4-(3-Chloro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-butoxy}benzoicacid

A solution of 5 mmol of intermediate product A4, 5 mmol of4-hydroxybenzoic acid and 20 mmol of potassium carbonate in 50 ml of DMFis stirred for 18 h at RT after which the solution is poured into water.This aqueous solution is washed with diethyl ether twice andsubsequently acidified with hydrochloric acid. The acidified solution isextracted with diethyl ether (3×) and the organic solution is dried overmagnesium sulfate. The compound crystallised on concentrating underreduced pressure. M. p. 169–171° C.

13.(cis)-4-[4-(3-Fluoro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-benzoicacid

A solution of 12 mmol of 4hydrazinobenzoic acid, 10 mmol of startingcompound A5 and 1 g of pyridine hydrochloride in 50 ml of pyridine isrefluxed for 18 h after which the solvent is evaporated. The residue isdissolved in dichloromethane and this solution is washed with 1Nhydrochloric acid. The organic phase is dried over magnesium sulfate andevaporated. The residue is crystallised from diethyl ether. M p.201–203° C.

14.(cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}-benzoicacid

A solution of 8 g of starting compound A6 and 8 g of 4-hydrazinobenzoicacid in a mixture of 100 ml of 1-propanol and 5 ml of triethylamine isrefluxed for 18 h. After evaporating the solvent, the residue ispartitioned between diluted hydrochloric acid and dichloromethane. Theorganic layer is dried over magnesium sulfate and evaporated. Theresidue is purified by chromatography (ethyl acetate). Crystallisationfrom diethyl ether. M. p. 222–224° C.

15.(cis)-4-{4-(3-bromo-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}-benzoicacid

Prepared from 4-hydrazinobenzoic acid and starting compound A10 asdescribed for compound 13.

M. p. 231–234° C.

16.(cis)-4-(3-chloro-4-methoxy-phenyl)-2-quinoxalin-2-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from quinoxalin-2-yl-hydrazine and starting compound A6 asdescribed for compound 7. M. p. 172–174° C.

17.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from (1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-hydrazineand starting compound A6 as described for compound 7. M. p. 217–219° C.

18.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from (3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)-hydrazine andstarting compound A6 as described for compound 7. M. p. 254–256° C.

19. (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,1-dioxo-tetrahydro-1l⁶-thiophen-3-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from (1,1-dioxo-tetrahydro-1l⁶-thiophen-3-yl)-hydrazine andstarting compound A6 as described for compound 7. M. p. 181–184° C.

20. (cis)-4o-3-Chloro -4nethoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from phenythydrazine and starting compound A11 as described forcompound 7. M. p. 161–162° C.

21.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from phenylhydrazine and starting compound A6 as described forcompound 7. M. p. 151–152° C.

22.cis-4-(3-Chloro-4-methoxy-phenyl)-2-{1-[1-(2-oxo-imidazolidin-1-yl)-methanoyl]-piperidin-4-yl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

Prepared from intermediate product A1 and 2-oxo-imidazolidine-1-carbonylchloride as described for compound 1. M. p. 216–218° C.

Starting Compounds and Intermediate Products:

A1.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

A solution of 50 mmol of starting compound A6, 55 mmol ofpiperidin-4-yl-hydrazine dihydrochloride (intermediate product A7) and100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h.After cooling to RT, the precipitate is filtered off and dried. M. p.268–270° C.

A2.(cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}-benzoicacid

A solution of 8 g of starting compound A6 and 8 g of 4-hydrazinobenzoicacid in a mixture of 100 ml of 1-propanol and 5 ml of triethylamine isrefluxed for 18 h. After evaporating the solvent, the residue ispartitioned between diluted hydrochloric acid and dichloromethane. Theorganic layer is dried over magnesium sulfate and evaporated. Theresidue is purified by chromatography (ethyl acetate). Crystallisationfrom diethyl ether. M. p. 222–224° C.

A3.(cis)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8.8a-tetrahydro-2H-phthalazin-1-one

A solution of 50 mmol of starting compound A6 and 0.1 mol of hydrazinehydrate in 100 ml of ethanol is refluxed for 5 h. On cooling to RT thecompound precipitated. M. p. 201–204° C.

A4.(cis)-2-(4-bromo-butyl)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

12 mmol of sodium hydride is added to a solution of 10 mmol ofintermediate product A3 in 50 ml of DMF. The resulting mixture isstirred for 30 min after which 50 mmol of 1,4-dibrombutane is added. Theresulting mixture is stirred for 1 h and subsequently poured into water.Purified by chromatography (ethyl acetate:hexane/1:4) and crystallisedfrom hexane. M. p. 109–111° C.

A5. (cis)-2-(3-fluoro-4-methoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared analogously to starting compound A6 as described in WO99/47505using 2-fluoroanisole instead of 2-chloroanisole. M. p. 185–187° C.

A6. (cis)-2-(3-chloro-4methoxybenzoyl)-1,2,3,6-tetrahydrobenzolc acid

Prepared as described in WO99/47505.

A7. Piperidin-4-yl-hydrazine dihydrochloride

A mixture of 0.1 mole of4-(N′-tert-Butoxycarbonyl-hydrazinoypiperidine-1-carboxylic acidtert-butyl ester (intermediate product A8) and 150 ml of concentratedhydrochloric acid is heated at 90° C. for 60 min after which the clearsolution is evaporated. The residue is washed with tetrahydrofurane,filtered off and dried under vacuum. M. p. 256–259° C.

A8. 4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acidtert-butyl ester

150 ml of a solution of borohydride in tertahydrofurane (1.0 mol/l) isslowly added to a solution of 0.12 mole of4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester (intermediate product A9) in 100 ml of drytetrahydrofurane. After complete addition, the mixture is stirred foranother 30 min after which a 100 ml of water is added to destroy theexcess of borohydride. Subsequently the tetrahydrofurane is evaporatedand the resulting aqeous solution extracted with diethyl ether. Afterdrying the solvent over magnesium sulfate, the ether is evaporated. M.p.112–115° C.

A9. 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acid tert-butylester (commercially available) and 0.15 mole of tert-butylcarbazate in250 ml of hexane is stirred for 18 h at RT. The precipitate is filteredoff and dried under vacuum. M. p. 172–174° C.

A10. (cis)-2-(3-bromo-4-methoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

Prepared analogously to starting compound A6 as described in WO99/47505using 2-bromoanisole instead of 2-chloroanisole. M. p. 201–204 ° C.

A11. (cis)-2-(3-chloro-4-ethoxybenzoyl)-1,2,3.6-tetrahydrobenzoic acid

Prepared analogously to starting compound A6 as described in WO99/47505using 1-chloro-2-ethoxybenzene instead of 2-chloroanisole. M. p.123–125°C.

COMMERCIAL UTILITY

The second messenger cyclic AMP (CAMP) is well-known for inhibitinginflammatory and immunocompetent cells. The PDE4 isoenzyme is broadlyexpressed in cells involved in the initiation and propagation ofinflammatory diseases (H Tenor and C Schudt, in “PhosphodiesteraseInhibitors”, 21–40, “The Handbook of Immunopharmacology”, AcademicPress, 1996), and its inhibition leads to an increase of theintracellular cAMP concentration and thus to the inhibition of cellularactivation (J E Souness et al., Immunopharnacology 47: 127–162, 2000).

The antiinflammatory potential of PDE4 inhibitors in vivo in variousanimal models has been described (M M Teixeira, TiPS 18: 164–170, 1997).For the investigation of PDE4 inhibition on the cellular level (invitro), a large variety of proinflammatory responses can be measured.Examples are the superoxide production of neutrophilic (C Schudt et al.,Arch Pharmacol 344: 682–690, 1991) or eosinophilic (A Hatzelmann et al.,Brit J Pharmacol 114: 821–831, 1995) granulocytes, which can be measuredas luminol-enhanced chemiluminescence, or the synthesis of tumornecrosis factor-α in monocytes, macrophages or dendritic cells (Gantneret al., Brit J Pharmacol 121: 221–231, 1997, and Pulmonary PharmacolTherap 12: 377–386, 1999). In addition, the immunomodulatory potentialof PDE4 inhibitors is evident from the inhibition of T-cell responseslike cytokine synthesis or proliferation (DM Essayan, Biochem Pharmacol57: 965–973, 1999). Substances which inhibit the secretion of theafore-mentioned proinflammatory mediators are those which inhibit PDE4.PDE4 inhibition by the compounds according to the invention is thus acentral indicator for the suppression of inflammatory processes.

Of the 11 phosphodiesterase (PDE) isoenzymes which are presently known,PDE7 was described for the first time, as HCP1 (“high affinitycAMP-specific PDE”), in 1993 (Michaeli T, Bloom T J, Martins T, LoughneyK, Ferguson K, Riggs M, Rodgers L, Beavo J A and Wigler M, Isolation andcharacterization of a previously undetected human cAMP phosphodiesteraseby complementation of cAMP phosphodiesterase-deficient Saccharomycescerevisiae, J Biol Chem 268: 12925–12932, 1993). According to today'snomenclature, HCP1 is human PDE7A1; in addition to this, another humansplicing variant of the same gene (PDE7A 2) (Han P, Zhu X and MichaeliT, Altemative splicing of the high affinity cAMP-specificphosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart. JBiol Chem 272: 16152–16157, 1997) and a second human PDE7 gene (PDE7B)(Sasaki T, Kotera J, Yuasa K and Omori K, Identification of human PDE7B,a cAMP-specific phosphodiesterase Biochem Biophys Res Commun 271:575–583, 2000) were described in the subsequent years. Individualrepresentatives of the PDE7 isoenzyme are characterized by beingparticularly prominently expressed in specific areas of the brain(putamen, caudate nucleus), in skeletal muscle, in leukaemic T celllines and in naive CD4+ T cells. The induction of PDE7 has beendescribed as being an essential prerequisite for activating T cells (LiL, Yee C and Beavo J A, CD3- and CD28-dependent induction of PDE7required for T cell activation. Science 283: 848–851, 1999).

The compounds according to the invention have useful pharmacologicalproperties which make them industrially utilizable. As selective cyclicnucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4and 7), they are suitable on the one hand as bronchial therapeutics (forthe treatment of airway obstructions on account of their dilating actionbut also on account of their respiratory rate- or respiratorydrive-increasing action) and for the removal of erectile dysfunction onaccount of their vascular dilating action, but on the other handespecially for the treatment of disorders, in particular of aninflammatory nature, e.g. of the airways (asthma prophylaxis), of theskin, of the intestine, of the eyes, of the CNS and of the joints, whichare mediated by mediators such as histamine, PAF (platelet-activatingfactor), arachidonic acid derivatives such as leukotrienes andprostaglandins, cytokines, T-cells, interleukins, chemokines, alpha-,beta- and gamma-interferon, tumor necrosis factor (TNF) or oxygen freeradicals and proteases.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed in human and veterinary medicine astherapeutics, where they can be used, for example, for the treatment andprophylaxis of the following Illnesses: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of varying origin(bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD);dermatoses (especially of proliferative, inflammatory and allergic type)such as psoriasis (vulgaris), toxic and allergic contact eczema, atopiceczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in theanogenital area, alopecia areata, hypertrophic scars, discoid lupuserythematosus, follicular and widespread pyodermias, endogenous andexogenous acne, acne rosacea and other proliferative, inflammatory andallergic skin disorders; disorders which are based on an excessiverelease of TNF and leukotrienes, for example disorders of the arthritistype (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis andother arthritic conditions), disorders of the immune system (AIDS,multiple sclerosis), graft versus host reaction, allograft rejections,types of shock (septic shock, endotoxin shock, gram-negative sepsis,toxic shock syndrome and ARDS (adult respiratory distress syndrome)) andalso generalized inflammations in the gastrointestinal region (Crohn'sdisease and ulcerative coltis); disorders which are based on allergicand/or chronic, immunological false reactions in the region of the upperairways (pharynx, nose) and the adjacent regions (paranasal sinuses,eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,allergic conjunctiyltis and also nasal polyps; but also disorders of theheart which can be treated by PDE inhibitors, such as cardiacinsufficiency, or disorders which can be treated on account of thetissue-relaxant action of the PDE inhibitors, such as, for example,erectile dysfunction or colics of the kidneys and of the ureters inconnection with kidney stones. In addition, the compounds of theinvention are useful in the treatment of diabetes insipidus andconditions associated with cerebral metabolic inhibition, such ascerebral senility, senile dementia (Alzheimer's disease), memoryimpairment associated with Parkinson's disease or multiinfarct dementia;and also illnesses of the central nervous system, such as depressions orarteriosclerotic dementia.

Particularly on account of their PDE7-inhibiting properties, thecompounds according to the invention are suitable for treating T-cellmediated diseases of inflammatory nature, for example of the kidney(glomerulonephritis) or of the pancreas (autoimmune diabetes) and,furthermore, for inhibiting the degenerative proliferation of T cells invarious forms of T cell leukaemia. In addition, the said compounds areof potential value in treating certain diseases of the brain (such asepilepsy) and of the skeletal muscle (such as muscular atrophy).

The compounds according to the invention are distinguished by a lowtoxicity, a good enteral absorption (high bioavailability), a largetherapeutic breadth and the absence of significant side effects.

The invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the abovementionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention also relates to the use of the compounds according to theinvention for the production of medicaments which are employed for thetreatment and/or prophylaxis of the illnesses mentioned.

The invention furthermore relates to medicaments for the treatmentand/or prophylaxis of the illnesses mentioned, which contain one or moreof the compounds according to the invention.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterases of type 4 and 7 (PDE4/7), ameliorating thesymptoms of an PDE4- and/or PDE7-mediated disorder, and wherein thepackaging material comprises a label or package insert which indicatesthat the pharmaceutical agent is useful for preventing or treating PDE4-and/or PDE7-mediated disorders, and wherein said pharmaceutical agentcomprises one or more compounds of formula I according to the invention.The packaging material, label and package insert otherwise parallel orresemble what is generally regarded as standard packaging material,labels and package inserts for pharmaceuticals having related utilities.

The medicaments are prepared by processes which are known per se andfamiliar to the person skilled in the art. As medicaments, the compoundsaccording to the invention (=active compounds) are either employed assuch, or preferably in combination with suitable pharmaceuticalauxiliaries and/or excipients, e.g. In the form of tablets, coatedtablets, capsules, caplets, suppositories, patches (e.g. as TTS),emulsions, suspensions, gels or solutions, the active compound contentadvantageously being between 0.1 and 95% and where, by the appropriatechoice of the auxiliaries and/or excipients, a pharmaceuticaladministration form (e.g. a delayed release form or an enteric form)exactly suited to the active compound and/or to the desired onset ofaction can be achieved.

The person skilled in the art is familiar with auxiliaries or excipientswhich are suitable for the desired pharmaceutical formulations onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

The administration of the medicaments according to the invention may beperformed in any of the generally accepted modes of administrationavailable in the art. Illustrative examples of suitable modes ofadministration include intravenous, oral, nasal, parenteral, topical,transdermal and rectal delivery. Oral and intravenous delivery arepreferred.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantagously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patent. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic deylces emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosemedicaments which are suitable for topical application. For theproduction of the medicaments, the compounds according to the invention(=active compounds) are preferably mixed with suitable pharmaceuticalauxiliaries and further processed to give suitable pharmaceuticalformulations. Suitable pharmaceutical formulations are, for example,powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by processesknown per se. The dosage of the active compounds is carried out in theorder of magnitude customary for PDE inhibitors. Topical applicationforms (such as ointments) for the treatment of dermatoses thus containthe active compounds in a concentration of, for example, 0.1–99%. Thedose for administration by inhalation is customarly between 0.1 and 3 mgper day. The customary dose in the case of systemic therapy (p.o. ori.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

Method for Measuring Inhibition of PDE4 and PDE7 Activities

The cDNA for PDE7A1 (Genebank Acc. No. L12052) was isolated, usingRT-PCR, from total cellular RNA derived from the T cell line CCRF-CEMand cloned into the cloning vector pCR2.1 (invitrogen, Groningen, NL)under standard conditions (the manufacturer's instructions). Forexpression in insect cells, the cDNA was subcloned into the baculoexpression vector pCRBac (invitrogen, Groningen, NL). The cDNA forPDE4D3 was a gift of Marco Conti (Stanford University, USA). The ORF(Genebank Acc. No. U50159) was cut from the original pCMV5 vector withthe restriction enzymes EcoRI and XbaI and subcloned in the expressionvector pBacPak9 (Clontech, Palo Alto).

The recombinant baculoylrus was prepared by means of homologousrecombination in SF9 insect cells. The expression plasmids werecotransfected with Bac-N-Blue (invitrogen, Groningen, NL) or Baculo-GoldDNA (Pharmingen, Hamburg) using a standard protocol (Pharmingen,Hamburg). Wt virus-free recombinant virus supernatants were selectedusing plaque assay methods. After that, high-titre virus supernatantswere prepared by amplifying 3 times. PDEs were expressed in SF21 cellsby infecting 2×10⁶ cells/ml with an MOI (multiplicity of infection)between 2 and 5 in serum-free SF900 medium (Life Technologies, Paisley,UK). The cells were cultured at 28° C. for 48 hours, after which theywere pelleted for 5–10 min at 1000 g and 4° C. In the case of PDE7A1cells were cultured in spinner flasks at a rotational speed of 75 rpm.

The SF21 insect cells were resuspended, at a concentration of approx.10⁷ cells/ml, in ice-cold (4° C.) homogenization buffer (20 mM Tris, pH8.2, containing the following additions: 140 mM NaCl, 3.8 mM KCl, 1 mMEGTA, 1 mM MgCl₂, 1 mM β-mercaptoethanol, 2 mM benzamidine, 0.4 mMPefablock, 10 μM leupeptin, 10 μM pepstatin A, 5 μM trypsin inhibitor)and disrupted by ultrasonication. The homogenate was then centrifugedfor 10 min at 1000×g and the supernatant was stored at −80° C. untilsubsequent use (see below). The protein content was determined by theBradford method (BioRad, Munich) using BSA as the standard.

PDE7A1 and PDE4D3 activities were inhibited by the said compounds in amodified SPA (scintillation proximity assay) test, supplied by AmershamPharmacia Biotech (see procedural instructions “phosphodiesterase[3H]cAMP SPA enzyme assay, code TRKQ 7090”), carried out in 96-wellmicrotitre plates (MTP's). The test volume is 100 μl and contains 20 mMTris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mMMg²⁺, 0.5 μM cAMP (including about 50,000 cpm of [3H]cAMP), 2 μl of therespective substance dilution in DMSO and sufficient recombinant PDE(1000×g supernatant, see above) to ensure that 15–20% of the cAMP isconverted under the said experimental conditions. After a preincubationof 5 min at 37° C., the reaction is started by adding the substrate(cAMP) and the assays are incubated for a further 15 min; after that,they are stopped by adding SPA beads (50 μl). In accordance with themanufacturer's instructions, the SPA beads had preylously beenresuspended in water and then diluted 1:3 (v/v); the diluted solutionalso contains 3 mM IBMX. After the beads have been sedimented (>30 min),the MTP's are analyzed in commercially available measuring appliancesand the corresponding IC50 values of the compounds for the inhibition ofPDE activities are determined from the concentration-effect curves bymeans of non-linear regression.

The inhibitory values determined for the compounds according to theinvention follow from the following table A, in which the numbers of thecompounds correspond to the numbers of the examples.

TABLE A Inhibition of PDE4 and PDE7 acitivity [measured as −logIC₅₀(mol/l)] PDE4 PDE7 Compound −logIC₅₀ (mol/l) −logIC₅₀ (mol/l) 1 8.647.64 2 8.4 6.97 3 8.25 6.74 4 8.61 7.38 5 7.86 7.18 6 7.64 7.08 7 8.096.98 8 8.05 7.05 9 8.59 7.54 10 9.11 7.73 11 9.05 6.57 12 8.19 7.01 137.34 6.42 17 7.66 7.38 18 7.63 7.11

1. A compound of formula I

in which R1 is methoxy or ethoxy, R2 is chlorine, bromine or fluorine R3and R4 together form an additional bond, R5 is R6, —C_(m)H_(2m)—R7,—C_(p)H_(2p)—Y-Aryl1, R12 or R26 in which R6 3-6C-cycloalkyl,3-7C-cycloalkylmethyl, quinoxalinyl, indazolyl, benzothiazolyl,6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,3-thiophen-2-yl[1,2,4]-thiadiazol-5-yl,1,1-dioxide-tetrabydrothiophen-3-yl,1-oxo-1,3-dihydroisobenzofuran-5-yl, 4-(4-yl-but-1-oxy)-benzoic acid, oran unsubstituted or by R61 substituted phenyl radical, in which R61 is1-4C-alkyl, 1-4C-alkoxy, carboxyl or 1-4C-alkoxycarbonyl, R7 iscarboxyphenyloxy, Y is a bond, Aryl1 is imidazolyl, m is an integer from1 to 4, p is an integer from 1 to 4, R12 is a radical of formula (a)

wherein R13 is —S(O)₂—R14, —C(O)R17 or Aryl3-1-4C-alkyl, R14 is phenylor phenyl substituted by R22, R17 is 1-4C-alkyl, 2-oxo-imidazolidin-1-ylor —N(R20)R21, R20 and R21 are independent from each other 1-7C-alkyl,or R20 and R21 together and with inclusion of the nitrogen atom to whichthey are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-or 1-hexahydroazepino-ring, R22 is 1-4C-alkyl, Aryl3 is pyridyl, R26 isa radical of formula (c)

wherein R27 is —(CH₂)_(u)R30, R30 is —N(R32)R33, R32 is 1-4C-alkyl, R33is 1-4C-alkyl, or R32 and R33 together and with inclusion of thenitrogen atom to which they are bonded, form a 4-morpholinyl-,1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, u is aninteger from 1 to 4, v is 1, X is —C(O)—, or a salt of thereof.
 2. Acompound of formula I according to claim 1 in which R1 is methoxy orethoxy, R2 is chlorine, bromine or fluorine, R3 and R4 together form anadditional bond, R5 is 1-(morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl, benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid,4-hydroxycarbonylphenyl or1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl, or a saltthereof.
 3. A compound of formula I according to claim 1 in which R1 ismethoxy or ethoxy, R2 is chlorine, R3 and R4 together form an additionalbond, R5 is 1-(morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl, benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid,4-hydroxycarbonylphenyl or1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl, or a saltthereof.
 4. A compound of formula I according to claim 1 selected fromthe group consisting of(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-2-(1-Acetyl-piperidin-4-yl)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(6-methyl-3-trifluoromethyl-pyridin-2-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-2-Benzothiazol-6-yl-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1H-indazol-5-yl)4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-cyclopentyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-imidazol-1-yl-butyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-{4-[4-(3-Chloro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-butoxy}-benzoicacid, (cis)-4-[4-(3-Fluoro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-benzoic acid,(cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzoicacid,(cis)-4-{4-(3-bromo-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}benzoicacid,(cis)-4-(3-chloro-4-methoxy-phenyl)-2-quinoxalin-2-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,1-dioxo-tetrahydro-1l(6)-thiophen-3-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-ethoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-{1-[1-(2-oxo-imidazolidin-1-yl)-methanoyl]-piperidin-4-yl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,and the salts of these compounds.
 5. A compound of formula I accordingto claim 1 in which R1 is methoxy or ethoxy, R2 is chlorine, R3 and R4together form an additional bond, R5 is1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl, 1,3,4trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl, 2-benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid orhydroxycarbonylphen-4-yl, or a salt thereof.
 6. A compound of formula Iaccording to claim 1 in which R1 is methoxy, R2 is chlorine, R3 and R4together form an additional bond, R5 is1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,6-methyl-3-trifluoromethyl-pyridin-2-yl, 2-benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid orhydroxycarbonylphen-4-yl, or a salt thereof.
 7. A compound of formula Iaccording to claim 1 in which the hydrogen atoms in the positions 4a and8a are cis-configurated.
 8. A compound of formula I according to claim 1in which the absolute configuration (according to the rules of Cahn,ingold and Prelog) is S in the position 4a and R in the position 8a. 9.A method of treating a disease or disorder in a patient comprisingadministering to a patient in need thereof a compound of formula Iaccording to claim 1, or a pharmacologically acceptable salt thereof,wherein the disease or disorder is selected from the group consisting ofasthma, COPD, rheumatoid arthritis, psoriasis, atopic eczema and Crohn'sdisease.
 10. A pharmaceutical composition comprising one or morecompounds of formula I according to claim 1, or a pharmacologicallyacceptable salt thereof, together with a pharmaceutically acceptableauxiliaries or carrier material.
 11. A method of treating an airwaydisorder in a patient comprising administering to a patient in needthereof an effective amount of a compound of formula I according toclaim 1, or a pharmacologically acceptable salt thereof, wherein thedisease or disorder is selected from the group consisting of asthma andCOPD.
 12. A method of treating a disease or disorder in a patientcomprising administering to a patient in need thereof a compound offormula I according to claim 4, or a pharmacologically acceptable saltthereof, wherein the disease or disorder is selected from the groupconsisting of asthma, COPD, rheumatoid arthritis, psoriasis, atopiceczema and Crohn's disease.
 13. A pharmaceutical composition comprisingone or more compounds of formula I according to claim 4, or apharmacologically acceptable salt thereof, together with apharmaceutically acceptable excipient or carrier material.
 14. A methodof treating an airway disorder in a patient comprising administering toa patient in need thereof an effective amount of a compound of formula Iaccording to claim 4, or a pharmacologically acceptable salt thereof,wherein the disease or disorder is selected from the group consisting ofasthma and COPD.